tbuckley/cabot-search huggingface dataset:
Impact of specific oncologic and geriatric parameters in predicting chemotherapy toxicity and death in elderly cancer patients.
Authors: Dani E Gholam, Elie Stephan, Nazem Bassil, Kamal El Haddad, Diane Antonios, Zeina Gerges, Amale Chebib, Mazen Haydar, Rana El Bikai
Journal: Journal of Clinical Oncology (2022)

e24026 Background: Cancer is mainly a disease of the elderly with more than 75% of patients aged 65 years and more at diagnosis. Comprehensive geriatric assessment (CGA) is usually used to assess elderly cancer patients¹. However, its sensitivity in predicting their outcome is questionable. Methods: We investigated whether specific oncologic and geriatric markers could predict chemotherapy toxicity and cancer-related death in a prospective single center study with 110 chemo-naive patients with advanced cancer. All patients underwent a CGA. Frailty markers as defined by Fried 2 as well as basic oncologic data were collected. Bivariate and multivariate analysis were done to assess the relation between the different variables and major toxicity. A Cox regression model for survival analysis was also performed. Results: Median age is 74 years [65-90 years]. 46% have stage IV disease. 27% have aggressive cancer as defined by Hurria et al 3 . Grade III-IX chemotherapy-related toxicity occurred in 22% of patients. Combined chemotherapy drug regimens, loss of appetite in the last 3 months and polypharmacy at baseline were predictive of chemotherapy toxicity in multivariate analysis. After a median follow-up of 12 months, 59% died of disease progression. In multivariate analysis, advanced cancer stage, initial loss of &gt; 5% body weight within 1 year, altered physical activity and Activity of Daily Living (ADL), anemia and heavy comorbidities (CIRS – G score) were predictive of poor outcome (Table). Conclusions: In elderly cancer patients, poor nutritional status and heavy comorbidities are predictive of both chemotherapy intolerance and death. In addition, markers such as anemia, advanced cancer stage, altered physical activity and impaired ADL predict early death. Balducci L. The Oncologist 2000. Fried LP. J Gerontol A Biol Sci Med Sci 2001. Hurria A. J Clin Oncol 2011. Clinical trial information: 02-02-18. [Table: see text]
Radiomic features on MRI enable progression risk in patients on active surveillance: Preliminary findings
Authors: A. Totaro, M. Campetella, E. Scarciglia, S. Vocino, L. Boldrini, V. Di Paola, R. Manfredi, F.P. Bizzarri, A. Cretì, L. Cosenza, R. Bientinesi, F. Pinto, E. Sacco, D. Cusumano, P. Bassi
Journal: European Urology (2022)
Rictor is a central target of the molecular network of cardiac ProtectomiRs
Authors: A Makkos, B Agg, ZV Varga, Z Giricz, M Gyongyosi, D Lukovic, R Schulz, M Bartekova, A Gorbe, P Ferdinandy
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Research, Development and Innovation Office of Hungary (NKFIA; NVKP-16-1-2016-0017 National Heart Program and OTKA-FK 134751); MTA-SE System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, H-1089 Budapest, Hungary We have previously identified several cardiac microRNAs that are involved in cardioprotection and termed them as ProtectomiRs. mRNA targets of these ProtectomiRs may reveal new drug targets for cardioprotection. Here we aimed to identify key molecular targets of ProtectomiRs and confirm their association with cardioprotection in a translational pig model of acute myocardial infarction. Network theoretical approach was utilized to identify 882 potential target genes of 18 previously described protectomiRs. Rictor gene was the most central and it was ranked first in the protectomiR-target mRNA molecular network with the highest node degree of 5. Therefore, expression of Rictor and its targeting microRNAs were further validated in heart samples obtained from a translational pig model of acute myocardial infarction and cardioprotection induced by pre- or postconditioning. Three out of five Rictor-targeting pig homologue of rat ProtectomiRs showed significant upregulation in postconditioned but not in preconditioned pig hearts. Rictor was downregulated at the mRNA and protein level in ischemic postconditioning but not in ischemic preconditioning. This is the first demonstration that Rictor is the central molecular target of ProtectomiRs and that decreased Rictor expression may regulate ischemic postconditioning-, but not preconditioning-induced acute cardioprotection. We conclude that Rictor is a potential novel drug target for acute cardioprotection.
Increased thermogenesis in hairless SHR is associated with enhanced myocardial connexin-43 signaling and suppression of pro-fibrotic signaling
Authors: K Andelova, B Szeiffova Bacova, M Sykora, S Pavelka, M Pravenec, M Barancik, N Tribulova
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Scientific Grant Agency of the Ministry of Education, Science, Research and Sport of the Slovak Republic VEGA 2/0158/19, 2/0002/20 and Slovak Research and Development Agency APVV 18-0548,19-0317 Background We have previously shown that downregulation of myocardial gap junction channel protein, connexin-43 (Cx43), and up-regulation of extracellular matrix (ECM) proteins in spontaneously hypertensive rats (SHR) hearts promote occurrence of lethal arrhythmia. Cold acclimation has a potential for reducing cardiovascular risk but there is a gap of knowledge concern the heart response to adaptive thermogenesis. Purpose To explore myocardial Cx43 and ECM proteins in genetically hairless strain of SHR, that represents rewarding model of increased adaptive thermogenesis. Methods Adult hairless males and females SHRM strain that harbors mutated desmoglein-4 gene and their wild type SHR were housed at standard 22 °C (that is below thermo-neutrality for these animals) and 12:12 hour light: dark cycle. WKY control rats were used as reference normotensive strain. Heart samples of the left ventricular tissue from euthanatized rats were used for the proteomics of Cx43, protein kinases, which phosphorylates Cx43, and for ECM markers TGF-β, SMAD2/3, MMP-2, collagen-1. Immunofluoresence detection of Cx43 was performed to examine its myocardial topology. Key Results Cx43 protein and its phosphorylatetd status was reduced in males and females SHR vs WKY rat hearts. In contrast, adaptive thermogenesis resulted in increased both parameters in SHRM regardless the sex. Moreover, pathological topology of Cx43 attributed to its enhanced localization at lateral sides of the cardiomyocytes in SHR was attenuated in SHRM. In addition, there were gentle differences in protein levels of PKA, PKG, PKCε, MAPK, Akt between SHR and SHRM. Protein level of TGF-β and SMAD2/3 were increased in SHR vs WKY rat hearts but decreased in SHRM unlike collagen-1 that was not altered in SHRM vs SHR. Conclusion Findings revealed beneficial up-regulation of myocardial Cx43 along with down-regulation of extracellular matrix proteins in response of hairless SHR to increased thermogenesis.
QOL-33. Adaptive behaviour of patients treated for malignant brain tumor in the first three years of life
Authors: Simonetta Giaquinta, Marta Tremolada, Bartolomeo Rossi, Alessandra Biffi, Elisabetta Viscardi
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Adaptive behavior is defined as the effectiveness and degree to which an individual meets social/cultural standards of personal independence and social responsibility. Patients treated for brain tumor are at risk of alteration of adaptive behaviour that, with a reduced intellectual function, makes diagnosis of mental retard. OBJECTIVE: The aim of this study was to evaluate the adaptive behaviour of patients treated for malignant brain tumor in the first three years of life and the variables that may correlate with its alteration. PATIENTS AND METHODS: Twelve survivors of brain tumor diagnosed in the first three years of life followed in the Pediatric Hematology and Oncology Department of Padua between January 2000 and December 2020 were enrolled in this study. We defined the level of the adaptive behaviour by evaluation adaptive behavior questionnaire (ABAS II) completed by the parents. RESULTS: None of the patients shows a high level of adaptive behavior. Preliminary evidences suggest that, the level of adaptive behavior may be influenced by the sex, irradiation and time from the end of treatment. In details, females show a higher level of performance than males, patients not treated with radiotherapy performed better than patients irradiated and longer-term survivors have a better level of adaptive behaviour. CONCLUSIONS: This study confirms that patients treated for brain tumor show a lower level of adaptive behaviour than peers. The future objective is to assess adaptive behaviour at many times to recognize the problem early.
Endoscopic balloon cryoablation against single instillation after transurethral resection of bladder cancer: A multicenter, randomized, controlled noninferiority trial.
Authors: Chenyang Xu, Haowen Jiang, Jianming Guo, Guowei Shi, Danfeng Xu
Journal: Journal of Clinical Oncology (2022)

e16561 Background: Cryotherapy is a prevalent percutaneous ablative therapy for solid tumors. However, studies on the clinical practice of endoscopic cryotherapy for intraluminal malignancies are lacking. We aim to explore the feasibility of endoscopic cryotherapy for bladder cancer. Methods: In this multicenter, randomized, parallel controlled, non-inferiority trial, we compared endoscopic balloon cryoablation (EBCA) with a single instillation (SI) of pirarubicin after transurethral resection (TUR).Men or women aged 18-85 years with a clinical diagnosis of bladder cancer (tumor number no more than 3 and maximal tumor size no more than 3 cm) were included. The exclusion criteria were as follows: locally advanced urinary bladder cancer (clinical stage T3 or T4), lymph node involvement (N1) or distant metastasis (M1), severe organ dysfunction, severe coagulation disorder, sepsis, concomitant neoplastic malignancy and other conditions unsuitable for surgery or intravesical chemotherapy. Women in pregnancy or lactation were also excluded. Eligible participants were randomly assigned (1:1) to the TUR-EBCA or TUR-SI group. The primary endpoint was the residual-free rate at repeated TUR. A non-inferiority test was used to compare the primary endpoint with a chosen margin of 10%. The secondary endpoints included the recurrence-free survival (RFS), progression-free survival (PFS) and adverse events. Results: We recruited 227 participants between November, 2017, and September, 2020. In total, 205 patients received EBCA or SI after TUR, of whom 163 completed all the required interventions and follow-up. In the per-protocol analyses, 75 (91.5%) of 82 patients had no residual tumor in the TUR-EBCA group compared with 61 (76.5%) of 81 in the TUR-SI group (risk difference 14.9%; 95% confidence interval [CI] 0.03 to 0.27, P &lt; 0.001), meeting the criteria for non-inferiority. Similar results were found in the after intention-to-treat analysis. After a median follow-up of 21 months, the TUR-EBCA group had better RFS(HR = 0.49; 95% confidence interval [CI] 0.24 to 0.99; Log-rank P = 0.046) and PFS (HR = 0.25; 95% confidence interval [CI] 0.08 to 0.77; Log-rank P = 0.0092). There were no significant differences in the SAEs rate (3.0% vs. 3.9%, p = 0.52). Conclusions: EBCA is a safe and effective adjuvant alternative to TUR for bladder cancer with the potential advantage of “energetically resecting” the tumor base. Clinical trial information: NCT02760953.
Reply to A. Saraswathula et al and Z.V. Fong et al
Authors: Philip Baum, Jacopo Lenzi, Samantha Taber, Hauke Winter, Armin Wiegering
Journal: Journal of Clinical Oncology (2022)

We highly appreciate the editorial by Heiden and Kozower 1 and comments by Saraswathula et al 2 and Fong et al 3 on our study of the performance of hospital volumes and risk-standardized mortality ratios (RSMRs) as proxies for effectiveness in oncologic surgical care. 4RSMRs express the ratio of predicted-to-expected in-hospital mortality, multiplied by the national unadjusted rate.Our study suggested that RMSR can outperform volume in effectiveness, efficiency, and hospital availability.One main assertion made by Saraswathula et al 2 was that RSMR is not the appropriate measure for determining a hospital's performance, especially when the sample size is small.We have already addressed this concern in response to a piece by Bilimoria and Pawlik 5 in Nature Reviews Clinical Oncology.Therefore, we will not go into detail here but refer instead to our previous correspondence. 6Before finalizing our results, our team discussed the known challenges of how to handle small sample sizes.Figure 1 in our paper presents the percentage distribution of hospitals' RSMR-based mortality classes according to hospital volume-based classes. 4It is striking that almost none of the low-volume hospitals had a low RSMR.What we had was a very high overlap between low-volume and medium-RSMR/high-RSMR institutions, suggesting that a systematic overestimate is improbable.
Spatial transcriptomics characterization of hepatocellular carcinoma using Molecular Cartography.
Authors: Joseph Wang Franses, Irun Bhan, Cristina R. Ferrone, Genevieve Marie Boland, David Tsai Ting
Journal: Journal of Clinical Oncology (2022)

e16110 Background: The microenvironment within hepatocellular carcinoma (HCC) tumors is composed of interacting cancer cells, endothelial cells and other stromal cells, and immune cells. The emerging field of spatial transcriptomics enables the measurement of gene expression in specific regions within a tissue sample. This technique retains the spatial context of intact tissue, can provide deep biological insights into cell-cell interactions, tumor microenvironment, and tumor progression. Methods: Resolve Biosciences’ Molecular Cartography platform was used on serial fresh frozen sections obtained from treatment naïve, HCC samples, and matched non-cancerous control liver tissues. Results: Given the high sensitivity, single-cell resolution, and specificity of the platform, the gene profiles of the hepatic endothelial, mesenchymal and parenchymal cell were studied in-depth to characterize the tumor microenvironment. The data obtained from the analyses revealed several local interactions between cancer cells, endothelial cells, and immune cells. These interactions include both known immune checkpoints and angiogenesis drivers and novel interactions. Conclusions: A deeper in situ understanding of the interacting cellular components of the HCC microenvironment may give insight into the natural history (prognosis) of the disease, predict response to therapies that target the immune system and vasculature, and define novel targets for the next generation of drug development.
Triplet Therapy, Transplantation, and Maintenance until Progression in Myeloma
Authors: Paul G. Richardson, Susanna J. Jacobus, Edie A. Weller, Hani Hassoun, Sagar Lonial, Noopur S. Raje, Eva Medvedova, Philip L. McCarthy, Edward N. Libby, Peter M. Voorhees, Robert Z. Orlowski, Larry D. Anderson, Jeffrey A. Zonder, Carter P. Milner, Cristina Gasparetto, Mounzer E. Agha, Abdullah M. Khan, David D. Hurd, Krisstina Gowin, Rammurti T. Kamble, Sundar Jagannath, Nitya Nathwani, Melissa Alsina, R. Frank Cornell, Hamza Hashmi, Erica L. Campagnaro, Astrid C. Andreescu, Teresa Gentile, Michaela Liedtke, Kelly N. Godby, Adam D. Cohen, Thomas H. Openshaw, Marcelo C. Pasquini, Sergio A. Giralt, Jonathan L. Kaufman, Andrew J. Yee, Emma Scott, Pallawi Torka, Amy Foley, Mariateresa Fulciniti, Kyle Hebert, Mehmet K. Samur, Kelly Masone, Michelle E. Maglio, Andrea A. Zeytoonjian, Omar Nadeem, Robert L. Schlossman, Jacob P. Laubach, Claudia Paba-Prada, Irene M. Ghobrial, Aurore Perrot, Philippe Moreau, Hervé Avet-Loiseau, Michel Attal, Kenneth C. Anderson, Nikhil C. Munshi
Journal: New England Journal of Medicine (2022)

In patients with newly diagnosed multiple myeloma, the effect of adding autologous stem-cell transplantation (ASCT) to triplet therapy (lenalidomide, bortezomib, and dexamethasone [RVD]), followed by lenalidomide maintenance therapy until disease progression, is unknown.In this phase 3 trial, adults (18 to 65 years of age) with symptomatic myeloma received one cycle of RVD. We randomly assigned these patients, in a 1:1 ratio, to receive two additional RVD cycles plus stem-cell mobilization, followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Both groups received lenalidomide until disease progression, unacceptable side effects, or both. The primary end point was progression-free survival.Among 357 patients in the RVD-alone group and 365 in the transplantation group, at a median follow-up of 76.0 months, 328 events of disease progression or death occurred; the risk was 53% higher in the RVD-alone group than in the transplantation group (hazard ratio, 1.53; 95% confidence interval [CI], 1.23 to 1.91; P<0.001); median progression-free survival was 46.2 months and 67.5 months. The percentage of patients with a partial response or better was 95.0% in the RVD-alone group and 97.5% in the transplantation group (P = 0.55); 42.0% and 46.8%, respectively, had a complete response or better (P = 0.99). Treatment-related adverse events of grade 3 or higher occurred in 78.2% and 94.2%, respectively; 5-year survival was 79.2% and 80.7% (hazard ratio for death, 1.10; 95% CI, 0.73 to 1.65).Among adults with multiple myeloma, RVD plus ASCT was associated with longer progression-free survival than RVD alone. No overall survival benefit was observed. (Funded by the National Heart, Lung, and Blood Institute and others; DETERMINATION ClinicalTrials.gov number, NCT01208662.).
A neutrophil-biomimic platform for eradicating metastatic breast cancer stem-like cells by redox microenvironment modulation and hypoxia-triggered differentiation therapy
Authors: Yongchao Chu, Yifan Luo, Boyu Su, Chao Li, Qin Guo, Yiwen Zhang, Peixin Liu, Hongyi Chen, Zhenhao Zhao, Zheng Zhou, Yu Wang, Chen Jiang, Tao Sun
Journal: Acta Pharmaceutica Sinica B (2022)

Metastasis accounts for 90% of breast cancer deaths, where the lethality could be attributed to the poor drug accumulation at the metastatic loci. The tolerance to chemotherapy induced by breast cancer stem cells (BCSCs) and their particular redox microenvironment further aggravate the therapeutic dilemma. To be specific, therapy-resistant BCSCs can differentiate into heterogeneous tumor cells constantly, and simultaneously dynamic maintenance of redox homeostasis promote tumor cells to retro-differentiate into stem-like state in response to cytotoxic chemotherapy. Herein, we develop a specifically-designed biomimic platform employing neutrophil membrane as shell to inherit a neutrophil-like tumor-targeting capability, and anchored chemotherapeutic and BCSCs-differentiating reagents with nitroimidazole (NI) to yield two hypoxia-responsive prodrugs, which could be encapsulated into a polymeric nitroimidazole core. The platform can actively target the lung metastasis sites of triple negative breast cancer (TNBC), and release the escorted drugs upon being triggered by the hypoxia microenvironment. During the responsiveness, the differentiating agent could promote transferring BCSCs into non-BCSCs, and simultaneously the nitroimidazole moieties conjugated on the polymer and prodrugs could modulate the tumor microenvironment by depleting nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) and amplifying intracellular oxidative stress to prevent tumor cells retro-differentiation into BCSCs. In combination, the BCSCs differentiation and tumor microenvironment modulation synergistically could enhance the chemotherapeutic cytotoxicity, and remarkably suppress tumor growth and lung metastasis. Hopefully, this work can provide a new insight in to comprehensively treat TNBC and lung metastasis using a versatile platform.
MODL-21. Multi-omics investigation of medulloblastoma resistant models reveals functional association between intracellular regulatory networks and drug susceptibility
Authors: Elena Mariotto, Elena Rampazzo, Roberta Bortolozzi, Fatlum Rruga, Lorenzo Manfreda, Chiara Marchioro, Silvia Bresolin, Giampietro Viola, Luca Persano
Journal: Neuro-Oncology (2022)

Abstract Medulloblastoma (MB) is the most common malignant brain tumor of childhood. Despite high-dose radio/chemotherapy treatment, 15-30% of patients still display a high risk of tumor recurrence. In this context, the characterization of innovative cellular models resembling therapy-induced drug resistance represents an unprecedented opportunity for selecting relevant therapies for chemotherapy-refractory patients. In order to unveil the molecular mechanisms sustaining chemotherapy resistance in MB, we setup in vitro models of MB drug resistance by exposing Patient-Derived MB (PD-MB) cells to a combination of the commonly used chemotherapeutics for pediatric MB treatment. Integration of multi-omics data, including transcriptional, proteomic and kinase activation profiling, disclosed that drug resistant PD-MB cells are characterized by a significant deregulation of several cancer-related pathways converging to metabolism of xenobiotics, adaptation of the biochemical processes sustaining energetic metabolic demand, cell proliferation and survival, protein homeostasis, RNA processing and modification, and immune response. Moreover, this intriguing regulatory network was functionally associated to the response of drug-resistant MB cells to a large library of compounds through a semi-automated High-Throughput drug Screening (HTS) workflow, suggesting the antimetabolite class of drugs as relevant therapeutics displaying high selectivity and efficacy against resistant MB models, together with a significant synergistic action when combined with standard chemotherapeutic agents. Collectively, our results suggest that drug-resistant MB cells are subjected to a peculiar adaptation of multiple intracellular processes during adaptation to chemotherapy, which protects them from the toxic environment but, at the same time, provides targetable vulnerabilities for therapeutic purposes.
The impact of adjuvant chemotherapy on overall survival in patients with node-positive Upper Tract Urothelial Carcinoma (UTUC): Improving precision in medicine with a risk-stratified approach
Authors: F. Abdollah, A.J. Piontkowski, S. Morisetty, N. Corsi, S. Majdalany, I. Rakic, A. Sood, M. Jamil, D. Dalela, S. Arora, C. Rogers
Journal: European Urology (2022)